Reactions between an alkyl halide and the hypophosphorous acid derivative, bis(trimethylsilyl)hypophosphite, is previously known from K. Issleib et al., Z. anorg. Chem. 530 (1985), pp. 16-28.
A radical initiated reaction between a hypophosphorous acid and an alkene is disclosed in Deprèle, S., et al., J. Org. Chem., 2001, 66, 6745-6755. The reaction is a radical addition of hypophosphites to olefins and the radical reaction is initiated by trialkylboranes and oxygen.
Winqvist A., et al., Eur. J. Org. Chem., 2002, 1509-1515, describe, inter alia, synthesis of phosphinic acids from alkyl halides and bis(trimethylsilyl)hypophosphite. The publication describes the influence of the temperature during the reaction.
WO 01/41743 discloses (aminopropyl)methylphosphinic acids and the synthesis thereof starting from protected aminopropylhalides and a hypophosphorous acid derivative.
U.S. Pat. No. 2,724,718 and U.S. Pat. No. 4,632,741 disclose the synthesis of phosphinate salts through a radical addition of a hypophosphite salt to olefins by means of irradiation with UV light in the presence of a photoinitiator.
EP 1055676 discloses a process for the preparation of dialkylphosphinic acids by free radical-initiated reaction with olefins.
Many initiators in the collection of suitable radical initiators require heat addition for initiating the reaction. Also oxygen can be used as an initiator for a radical reaction. However, some of the hypophosphorous acid derivatives are pyrophoric and therefore oxygen is not a suitable initiator in large-scale production. One such example is the hypophosphorous acid derivative bis(trimethylsilyl)hypophosphite.
Chemical radical initiators would be possible for initiating the reaction between an alkyl halide and a hypophosphorous acid derivative. Most often, when such initiators are used, the reaction is started by raising the temperature of the reaction mixture. However, temperature is also a critical parameter for reduction of the amount of by-products, the lower temperature the lower amount of by-products. The disadvantage of lowering the temperature is that also the reaction rate is reduced at a low temperature, and this has implications for the result and the yield of the desired product. Therefore, there is a need for a process where the amount of by-products obtained are kept low in parallel with a fast and efficient reaction rate.
WO 2006/038870 discloses that UV-light can catalyze the reaction between alkyl iodides and BTHP in the formation of alkyl phosphinic acids. The use of UV-light is convenient on lab-scale, but it has proven to be difficult to find viable technical solutions on larger scales.
Outline of the Invention
The present invention relates to a new process for the synthesis of alkyl phosphinic acids starting from alkyl halides and a hypophosphorous acid derivative in the presence of an amine and an amineoxide.
More particularly, the present invention relates to a process for the synthesis of a compound of formula I
wherein
R1 is selected from hydrogen; C1-C10-alkyl; C1-C10-alkoxy; fluorine; and chlorine;
R2 is selected from hydroxy; fluorine; chlorine; oxo; and C1-C10-alkoxy;
R3 is selected from hydrogen and C1-C6-alkyl;
R4 is selected from hydrogen and C(O)R5;
R5 is selected from C1-C10 alkyl and C1-C10 alkoxy;
comprising reacting a compound of formula II

R6 is selected from hydrogen; C1-C10-alkyl; C1-C10-alkoxy; fluorine; and chlorine;
R7 is selected from hydroxy; fluorine; chlorine; oxo; and C1-C10-alkoxy;
R8 is selected from hydrogen and C1-C6-alkyl;
R9 is selected from hydrogen and C(O)R10;
R10 is selected from C1-C10 alkyl and C1-C10 alkoxy; and
X is iodide or bromide;
with a compound of formula III
wherein
to R11 and R12 are each and independently selected from C1-C10 alkyl and Si(R13)3;
and
R13 is a C1-C6 alkyl;
in the presence of an amine and an amineoxide.
When the substituent R2 and/or R7 is oxo, then this substituent is bound to the carbon atom by a double bond. In this case, no hydrogen atom is bound to said carbon atom.
In another embodiment, the compound of formula II is prepared by reacting another compound of formula II, wherein X is mesyloxy, with one or more halides.
In another embodiment, the halides are selected from sodium iodide and tetrabutylammonium iodide.
In another embodiment, the compound of formula I is

In another embodiment, the compound of formula II is

In another embodiment, the compound of formula III is bis(trimethylsilyl)hypophosphite.
In another embodiment, the amine is selected from hexamethyldisilazan, N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, and 2,2,6,6-tetramethylpiperidine.
In another embodiment, the amineoxide is selected from trimethylamineoxide, N-methylmorpholineoxide (NMM-oxide) and 2,2,6,6-tetramethylpiperidineoxy radical (TEMPO).
In another embodiment, the reaction is performed in the presence of toluene, tetrahydrofuran, acetonitrile, ethyl acetate or in a mixture thereof.
In another embodiment, the reaction is performed at a temperature of from −70° C. to 20° C.
In another embodiment, the reaction is performed at a temperature of from −70° C. to 0° C.
As used herein:
ACN refers to acetonitrile;
BTHP refers to bis(trimethylsilyl)hypophosphite;
DIPEA refers to diisopropyl ethyl amine;
EtOAc refers to ethyl acetate;
HPLC refers to high performance liquid chromatography;
IPC refers to in-process control;
MEK refers to methyl ethyl ketone;
NMM refers to N-methylmorpholine;
PEG refers to polyethylene glycol;
QI refers to tetrabutylammonium iodide;
TEMPO refers to 2,2,6,6-tetramethylpiperidineoxy radical;
THF refers to tetrahydrofuran;
TLC refers to thin layer chromatography.
According to the present invention, NMM is used in the reaction mentioned above as a base forming a precipitate with the hydrogen iodide generated in the reaction. NMM-oxide is used as a catalyst. Process development based on these findings resulted in a method that gives reproducible results on 1000-L scale, resulting in a shorter reaction time and a slightly higher yield.
Unless otherwise stated the term “C1-C10 alkyl” as used throughout this specification includes linear or branched C1-C10 alkyl. Examples of C1-C10 alkyl include, but are not limited to, C1-C6 alkyl such as methyl, ethyl, propyl, n-propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl.
Unless otherwise stated, the term “alkoxy” denotes an O-alkyl, wherein alkyl is as defined above. The term “C1-C10 alkoxy” as used throughout this specification includes linear or branched C1-C10 alkoxy. Examples of C1-C10 alkoxy include, but are not limited to, C1-C6 alkoxy such as methoxy, ethoxy, propoxy, n-propoxy, and tert-butoxy.
The synthesis of the phosphinic acids according to the present invention can be performed at temperatures at or below approximately room temperature, i.e. at a temperature of or below 20° C. The effect of lowering the temperature is that the various side reactions and the amount of by-products limiting the yield of the reaction can be reduced. According to one embodiment of the invention, the reaction mixture is held at a temperature of approximately 0° C. By lowering the reaction temperature to approximately −70° C. an increased yield can be achieved. Dehalogenation is a side reaction, which occurs. However, the dehalogenation is suppressed by lowering the temperature, and thus, the production of the sideproducts is suppressed.
An alkyl phosphinic acid is produced according to the present invention by adding the alkyl halide dissolved in a solvent which may be organic to a cooled solution comprising the hypophosphorous acid derivative in an inert environment, i.e. an environment free from oxygen attained by using nitrogen or argon.
The components for forming the hypophosphorous acid derivative, i.e. the hypophosphite to group, are, for example, ammonium hypophosphite and hexamethyldisilazan, ammonium hypophosphite, DIPEA and trimethylsilyl chloride. They are mixed in a vessel until the reaction is completed, the reaction mixture is then cooled and kept in an environment free from oxygen.
For example, when BTHP is being used as the hypophosphorous acid derivative, the first step of the synthesis for obtaining alkylphosphinic acids is the formation of BTHP. The formation of the hypophosphorous acid derivative just before the addition of the alkyl halide is an advantage since the hypophosphorous acid derivative is highly pyrophoric. The alkyl halide is then added and the reaction is thereafter initiated by NMM and NMM-oxide. The completion of the reaction is measured by, for example, HPLC or TLC.
During the process of the invention, a neutralisation of the hydrogen halide formed during the reaction can be performed by having a base present during the synthesis of the phosphinic acid. The base is suitably an amine such as hexamethyldisilazan, N-methylmorpholine, trimethylamine, triethylamine, or DIPEA.
The reaction is conducted in an aprotic organic solvent, for example, toluene, THF, EtOAc, acetonitrile, MEK, or in a mixture thereof.
The compound formed is recovered by extraction in a polar solvent such as ethyl acetate, isopropanol, n-butanol or a mixture thereof.
By mixture thereof is meant a mixture of two or more of said solvents.
The compounds synthesised according to the claimed process of the present invention can form salts with bases. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or those with ammonia or organic amines.
The process according to the present invention is an efficient as well as an economical process for the preparation of alkylphosphinic acids. The following Examples will further illustrate the invention, but are not intended to limit the scope of the invention as described herein or as claimed below.